Genetic assessment of dyslipidaemia

Hyperlipidaemia is most commonly associated with a variety of secondary causes (see “Classification of dyslipidaemia”) but investigations into less common inherited dyslipidaemias have progressed in recent years. Identification of the genetic mutations associated with these disorders helps to develop our understanding of the pathophysiology of lipid disorders and can play a role in the assessment of some patients.

Familial Hypercholesterolaemia

Autosomal dominant Familial Hypercholesterolaemia (FH) is one of the most common inherited metabolic diseases with a frequency of approximately 1:500 for heterozygotes and 1:1,000,000 for homozygotes. It is most commonly caused by mutations in the LDL receptor (LDLR) gene. Reduced LDLR number in hepatocytes or abnormal function of the LDLR result in reduced LDL clearance and therefore elevated serum LDL concentrations. Tendon xanthomata may be present and coronary artery disease tends to occur in the fourth or fifth decades in heterozygotes. Homozygote patients can develop coronary artery disease before the age of 20.

Familial defective apolipoprotein B is an autosomal codominant disorder caused by mutations in the apolipoprotein B (ApoB) gene and patients present with a very similar clinical picture to those with LDLR mutations. LDL cholesterol levels are approximately 20-25% lower than in FH patients with LDLR mutations. In addition, the patients with ApoB mutations generally respond better to statins and have lower cardiovascular risk. A third mutation that causes FH is in the gene that encodes proprotein convertase subtilisin/kexin type 9 (PCSK9). This is a serine protease that degrades hepatic LDLR and thus gain of function mutations cause increased serum LDL with similar clinical features to those patients with LDLR mutations.

Mutations in the LDLR adaptor protein (LDLRAP1) have been discovered in families with autosomal recessive hypercholesterolaemia (ARH). LDLRAP1 is essential for LDLR mediated endocytosis because it promotes clustering of LDLRs into clathrin coated pits on the surface of hepatocytes. Inactivating LDLRAP1 mutations result in retention of LDLRs on the cell surface and thus reduced LDL uptake. Mutations in two adjacent ATP binding cassette transporters, ABCG8 (sterolin 2) and ABCG5 (sterolin 1) have been discovered in patients with the condition sitosterolaemia. These transporters regulate sterol transport at the apical surface of hepatocytes and enterocytes. This condition is characterised by elevations in serum cholesterol along with high levels of plant sterols such as sitosterol. Mutations in these two genes lead to increased absorption and accumulation of cholesterol and plant sterols.

Genetic analysis is available for the common mutations that cause FH, though this can be relatively expensive. In practice, identification of the precise mutation in a patient and/or family that fulfil the diagnostic criteria for FH (Simon Broome criteria) is not always required because the results will not change subsequent management of the patient. DNA analysis can be helpful in cases where the diagnosis is uncertain, for example to confirm the diagnosis of FH in the child of an affected proband, who has borderline LDL results.

Familial dysbetalipoproteinaemia

Familial dysbetalipoproteinaemia (type III hyperlipoproteinaemia/broad β disease) is a rare condition caused by the presence of increased chylomicron remnants and IDL (collectively termed β VLDL) in the circulation. It is associated with increased rates of atherosclerosis. The incidence of coronary artery disease is similar to that in FH but peripheral arterial disease is much more common in familial dysbetalipoproteinaemia than in FH. The condition is inherited in an autosomal recessive fashion with variable penetrance. Polymorphism of the apoE gene results in impaired binding of apolipoprotein E to its receptor. The most common polymorphism (apoE2) involves substitution of an arginine residue for cysteine at position 158 of the peptide chain. 90% of patients with this condition are homozygous for the apoE2 polymorphism. Often the hyperlipidaemia does not manifest unless another condition predisposing to VLDL production (e.g. diabetes, excess alcohol, obesity) occurs.

In familial dysbetalipoproteinaemia both serum cholesterol and triglycerides are elevated, often in equimolar proportions. In addition, serum Apo B is not elevated in this condition and this often provides the clue to the diagnosis. Genetic assessment plays an important role in diagnosis of this condition. ApoE2 homozygosity can be identified using restriction fragment length polymorphism analysis and this confirms the diagnosis.

Genetics of hypertriglyceridaemia

Severe hypertriglyceridaemia can be caused by genetic deficiencies in Lipoprotein Lipase (LPL) activity. This rare condition usually presents in childhood and the severe hypertriglyceridaemia is accompanied by episodes of recurrent acute pancreatitis, eruptive cutaneous xanthomata and hepatosplenomegaly. Plasma appears milky because of increased triglyceride levels and chylomicrons are observed after the plasma has been left standing for several hours. Familial LPL deficiency is inherited in an autosomal recessive fashion and is caused by a mutation in the LPL gene. A similar clinical picture can result from an inherited deficiency of the LPL cofactor, apolipoprotein C II (Familial apolipoprotein C II deficiency). In families with familial LPL deficiency, carrier testing and prenatal diagnosis for at risk pregnancies can be performed if the disease causing mutation in the LPL gene is known (more than 200 mutations have been described).

Although genetic factors are certainly important in Familial Combined Hyperlipidaemia (FCHL), no single gene mutation has yet been identified. This condition is characterised by either isolated or combined hypercholesterolaemia and hypertriglyceridaemia in a patient with at least one first degree relative who also displays dyslipidaemia. Affected individuals have elevated levels of Apo B caused by increased secretion of VLDL particles, and elevated small, dense LDL.

Familial Hypoalphalipoproteinaemia

Familial Hypoalphalipoproteinaemia (FHA) is characterised by low HDL cholesterol in the presence of normal VLDL and LDL cholesterol concentrations, with a similar lipid pattern present in a first degree relative. Familial Apo A I deficiency is caused by deletion of the APOA1 gene and since Apo A I is the major protein component of HDL, HDL cholesterol concentrations can be undetectable in homozygotes with this condition. Familial lecithin cholesterol acyltransferase (LCAT) deficiency is a rare, autosomal recessive disorder characterised by corneal opacities, normochromic anaemia and renal failure. LCAT deficiency results in decreased esterification of cholesterol to cholesteryl esters on HDL particles with subsequent accumulation of free cholesterol on lipoprotein particles and in peripheral tissues such as the cornea (fish eye disease), red blood cells and renal glomeruli. Tangier disease is an autosomal codominant disorder that presents with extremely low HDL cholesterol concentrations. This condition can be caused by mutations in the ATP binding cassette transporter 1 (ABCA1), which mediates the efflux of cholesterol from cells. As a result, cholesteryl esters are deposited within tissues and patients present with enlarged, orange tonsils, peripheral neuropathy, splenomegaly and premature coronary heart disease.